Holy Grail

Merck KGaA (not to be confused with Merck & Co.) announced in a press release that they will be filing a marketing authorization application (MAA) to the European Medicines Agency (EMEA) for Cladribine Tablets (Mylinax). In the future EMD Serono (their subsidiary) will be submitting an NDA with the FDA.

Merck KGaA estimates that sales will be $1 billion.


I am not that such a rosy picture is justified.

Here’s why:

Biogen Idec (BIIB) and Elan’s (ELA) Natalizumab (Tysabri) had $481 in global sales in the first half of 2009; our estimate is that worldwide sales for 2009 will be between $1.057 and $1.1 billion. But, remember, this is a drug that has been on the market and is not new (with potentially new side effects).


So, let’s compare the advantages of Tysabri and Cladribine:

1. Tysabri has great efficacy (~60% better than placebo in SENTINEL and ~50% when combined with Avonex vs. Avonex alone in AFFIRM).
2. Tysabri is not an injectable and instead is into the vein (intravenous/IV).
3. Tysabri is well tolerated.
4. Tysabri has an easy dosing schedule and is only given 12 times a year.

On the other hand,

1. Cladribine is ~50% better than better than placebo in CLARITY.
2. Cladribine is the first oral
3. Cladribine is well tolerated.
4. Cladribine is taken 8 (to 20 – who knows what the regulators will finally say).


Wait! What about side effects?

Oh, I almost forgot to mention* (does that sound familiar?):

A. PML (progressive multifocal leukoencephalopathy) in Tysabri.
B. PCNSL (primary CNS lymphoma) in Tysabri (and rumors of two more – one in Germany and one in the U.S.).
C. Cancers in Cladribine (female cancers in a diagnosis that is 2/3 women and usually stats when they are young: ovarian, cervical and choriocarcinoma – as well as pancreatic cancer and melanoma).

So, what strategies are the representatives going to use to sell against each other (welcome to the interferon wars again)?

1. Efficacy:

a. EMD Serono is going to say that you can’t compare between trials.
b. Biogen Idec is going to say they are superior.

2. Oral vs. not:

a. EMD Serono is selling the first oral; he MS community has been waiting for this Holy Grail.
b. Biogen Idec is going to stress the convenience of being monitored for treatments, instead of possibly the dreaded “lost to follow-up”).

3. Tolerability:

a. EMD Serono is going to stress the lack of infusion reactions.
b. Biogen Idec is going to stress the patient advocates and their strong message of how Tysabri changed their lives (anecdotally, neurologists do sometimes see that patients on Tysabri have a reduction in their pain – but you didn’t hear this from the company).

4. Dosing:

a. EMD Serono is going to stress how seldomly a patient needs to take the medication and that they don’t need to come into an infusion center.
b. Biogen Idec is going to stress the lack of dose adjustments and the fact that Tysabri is only 12 times a year (they should have sold it this way from the beginning – it sounds a lot less than “monthly” or “every month”). It is difficult to forget a monthly infusion outside the home, while a pill you take a few times a year may be easily forgotten.

So, what are clinicians going to do?

Neurologists care about:

A. Efficacy:

a. Disability
b. Relapses

B. Safety:

a. We know how to reverse Tysabri with plasma exchange (plasmapheresis) but we don’t know what to do with Cladribine.
b. Future pregnancies: are there issues?
c. What to do next in patients who “fail” the medication (isn’t it the drug failing them?).
d. New unknown side effects (we are finally getting used to Tysabri).

C. Tolerability:

a. Are patients going to have problems leading to additional phone calls or problems?



Now this doesn’t even take into account the next oral medication, FTY720 (Fingolimod). A daily medication is more annoying than Cladribine, but also easier to remember. How many patients with hypertension forget to take their daily blood pressure medication and then have a heart attack or stroke? Also, Fingolimod is 50% better than Avonex – does this beat cladribine, and even Tysabri. What’s going to happen when there is a subcutaneous Tysabri – is it going to be more convenient because it will be given at home, or will it be seen as a regression back to injectable medications?



So what does this mean for the MS market, MS drugs, and most importantly the individual MS patient?


It depends who you ask.



Technical and Scientific Details:

Many people want to know how these medications work and what their mechanism of action is:

1. Interferons (Avonex, Betaseron, Rebif, Pegylated Avonex, Rebif New Formulation) – noone (no one) fully understands.

2. Glatiramer Acetate (Copaxone) – ditto.

3. Natalizumab (Tysabri) – A monoclonal antibody directed against the part (VLA4 / integrin) of the lining of the central nervous system (CNS) that sticks to white blood cells (lymphocytes). Thus reducing the amount of immune cells that get through the blood brain barrier).

4. Cladribine (Mylinax) – A molecule that is changed (phosphorylated) to a different form (its corresponding nucleotide CdATP), which accumulates in the lymphocytes and gets into their DNA. High levels of CdATP lead to DNA strand breaks, inhibition of DNA synthesis, and cell death.

5. FTY720 (Fingolimod) – Stops lymphocytes from leaving the lymph nodes; this keeps them away from the bloodstream and reaching the BBB; thereby reducing the immune attack on the brain, optic nerves and spinal cord (cervical and thoracic cord).


Now, for the rest of the emerging medications (Laquinomod, Teriflunomide, BG00012, MBP8298, Daclizumab, Campath, Rituximab, Ocrelizumab, …)** you will have to wait for more in the future.


* Why do these biotech companies seldomly (seldom) mention the serious side effects.
** The … is the most exciting advance of all (think pre-1993 …).




- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
http://www.neurologique.org/